Production of steroids



Patented Mar. 16, 1954 UNITED STATES, PATENT OFFICE- PRODUCTION OF STEROIDS Robert B. Woodward, Belmont, Mass., assignor to Research Corporation, New York, N. Y., a corporation of New York No Drawing. Application January 31, 1952,

Serial No. 269,329

3 Claims. (01. 260-586) a 2, a This invention relates to methods and com- I In the structure formulas in the chart, methyl pounds useful in the produ ti n 0 Steroids, D groups attached to carbon atoms common to two ticularly the adrenal cortical such as rings are indicated by the conventional line excortisone.

In the following Outline of the methods of the 5 tending from the carbon atom, and Ac indicates invention reference is had to the illustrative sethe residue of an Organic carboxylic d, Suc quence of novel compounds of the invention. I as acetic acid.

( OH (II) 0H (m a s 4 3 1 I I I l o o 0 H011 (v1 v 6 Ac (IV) (VII) (VIII) (IX) H l O C a O CH: 0 on 0 O O (XI) vertedito the tra'ns-adduct, trans-wmethoxyw 10-metliyl- 5,3, 9,l0--tetrahydro L l-naphthaquinone (I) by dissolving in an aqueous alkaline organic solvent and acidifying after seeding with the trans-isomer.

The trans-adduct is reduced to the corresponding glycol (II) with lithium aluminum hydride, and the glycol is converted to the ketol, l-hydroxy-Z-keto-lO-methyl l,2,5,8,9,10 hexahydronaphthalene (III), by treatment with a dilute mineral acid. The ketol is then esteritied (IV) with any organic carbokylic acid, for example,

acetic acid...

The ketol ester (IV) is reduced by treatment with zinc in acetic anhydride or in an inert organic solvent to 2-keto-10 methyl-1,2,5,8,9,10- hexahydronaphthalene,(VY. The bicyclic ketone (V) is formylated at position 1 to give the l-hydroxymethylene' derivative (VI), which iscondensed withr ethylvinylketone to give l-formyl-l-(p propionylethyD-2-keto lo-methyl- 1,2,53,53,10-hexahydronaphthalene (VII).

Treatment of compound (VII) with mild con- 'clehsing agents such as potassium hydroxide in The tricyclic ketone (VIII) is oxidized to the IH-glycol (IX).

ide typically gives the two cis-isomers both of which are usable in the succeeding steps of the Oxidation with osmium tetroxme,th od. Other oxidizing agents may give the (X), and protected compound hydrogenated at the 9,10-d0uble bond, for example, with hydrogen at atmospheric pressure in a non-polar solvent, such as dry benzene, in the presence of a hydrogenating catalyst, to produce the dihydro derivative (XI), which is formylated at position 3 (XII). The formyl group of compound (XII) is protected by reacting it with a secondary amine, such as methylaniline, to give the methylanilino derivative (XIII).

Compound XII is reacted with acrylom'trile in the presence of a quaternary nitrogen base to give the isomeric cyanoethyl compounds XIVa and XIVb, which are preferably not separated at this stage but are hydrolyzed to the corresponding carboxyethyl compounds. The keto acids may be separated by taking them up in ether. A keto acid (XVa) melting at 150 C. (labile) and 170 C. (stable) crystallizes from the ether and the other isomeric keto acid (XVb) is obtained as an oil by evaporation of the ether. The oily acid has the desired configuration at asymmetric carbon atom 1.

The keto acid (XVb) is converted to the enol lactone (XVI), for example, by boiling with acetic anhydride in the presence of a small amount of sodium acetate. The lactone (XVI) is now converted to the tetracyclic ketone (XVII), having a D-homosteroid ring structure by condensing wtih a methyl magnesium halide, decomposing the addition product with acid and treating the product thus obtained with dilute aqueous alkali in a water-miscible organic solvent.

The homo-D-ring of ketone (XVII) may now be converted to a cyclopentano ring by opening and reclosing the ring, for example, by the following steps: The ketone (XVII) is oxidized, for example, with H104, to the dialdehyde (XVIII), 1,2- bis(aldehydomethyl) 2,13 dimethyl 7 ketc- 1,2,3,5,6,7,9,10,11,13-decahydrophenanthrene, and the dialdehyde is condensed to the 17-aldehyde steroid, A9,(1l) ,16 bisdehydro 21 norprogesterone (XIX) by heating a solution of the dialdehyde in an organic solvent. Some of the isomeric 15-aldehyde (XIXa) is also formed. The aldehydes XIX and XIXa have the same steric configuration at the asymmetric carbon atoms as the natural steroid hormones of the adrenal cortex such as cortisone and may be converted into these hormones by already available procedures.

The following specific examples are illustrative of the methods and compounds of the invention:

Isomeriaation of the cisadduct to the transadduct.-Sixty grams of the cis-adduct (M. P.

9395 C.) obtained by the Diels-Alder condensation of 1,3-butadiene and 2-methyl-5-methoxybenzoquinone, purified by recrystallization and almost colorless, is dissolved in 80 ml. of dioxane. Solution is facilitated by warming to 40-50" C. Five per cent more than the calculated amount of about 1N sodium hydroxide solution (312 ml, 0.975N) is added over min. with stirring in an atmosphere of nitrogen. A brownish orange solution containing about 1 g. of suspended solid is obtained. This solution is diluted by the addition of 600 ml. of water and then seeded with 3 g. of finely powdered trans-adduct (M. P. 125-127 C.). At this point it is essential to ascertain that most of the seed has remained undissolved. If there be excess alkali present, the seed material will of course go into solution; in that case more trans-adduct should be added till there is an appreciable amount of undissolved solid in suspension. About 1N hydrochloric acid is added dropwise to the seeded solution with vigorous stirring; a solid starts to separate immediately. Addition of acid is stopped when the solution changes color to lemon yellow indicating complete neutralization (pH 5) of the base. Some more water (200 ml.) is added and the solid product is collected by filtration, washed four times with water and dried. A finely granular, light tan colored solid, M. P. 126-129 C., is obtained. This material is pure enough for use in the next step without further purification.

Glycol (II) .-The trans-adduct (I) g.) in dry pure redistilled tetrahydrofuran (1 l.) is slowly added to a stirred solution of lithium aluminum hydride (24 g.) in dry ether (1.4 l.) in an atmosphere of nitrogen. The addition is controlled so as to keep the mixture refluxing gently (addition time ca. 2% hrs.) During the addition a viscous sticky complex separates onto the stirrer, making stirring difiicult. The complex towards the end of the addition becomes more granular, and at the end a suspension of a white powder is obtained. Stirring is continued for a further /2 hour, and ethyl acetate is then slowly added to the ice-cooled stirred suspension until no more reaction is observed (the reaction is very exothermic and the ethyl acetate must be added very carefully).

After the excess LiA1H4 has been decomposed by the addition of ethyl acetate, a saturated solution of Na2SO4 is added dropwise, with stirring, to the reaction mixture. The white suspension soon becomes light yellow. During the entire addition of saturated sodium sulphate solution, rapid stirring is continued so that the LiAlH-i complex clinging to the sides of the flask may be washed down. Addition of the saturated solution is continued until the precipitate becomes slightly wet (at which time it starts clinging to the sides of the flask). Without stopping the stirring about 200 gms. MgSO4 (anhyd) are added. Rapid stirring is continued for another 10 minutes. The precipitate is then filtered from the ethereal solution and washed thoroughly with excess ethyl ether. The filtrate and washings are concentrated, last traces of solvent removed at the water pump, and the viscous oil obtained is diluted with a small amount of ethyl ether and allowed to crystallize in the refrigerator overgight. The crude glycol melts at about 128-433 Ketol (III) .-The crude glycol (68 g.) is dissolved fn reagent grade dioxan (375 cc.) and 2N sulfuric acid (300 cc.) is added. The solution is allowed to stand for 24 hours at room temperature and is then poured into ether and water. The aqueous layer is washed twice more with ether, the combined ether solutions are washed with sodium bicarbonate solution, and the latter extract is again extracted with ether. The combined ethereal layers are washed once with salt solution, dried (MgSOi), and evaporated. The remaining dioxan is completely removed on the water pump. The residue consisting of the crude ketol, partly solidifies on being seeded with a specimen of pure ketol (M. P. 71-72 0.).

Ketol acetate (IV) .The crude ketol (58 g.) is dissolved in dry pyridine (300 cc. reagent grade pyridine kept over potassium hydroxide for several days), and acetic anhydride (60 cc. reagent grade) is added. The solution from which moisture is excluded by a calcium chloride tube, is heated on the steam bath for a few minutes, and is then set aside overnight. Most of the pyridine is removed from the red solution at the water pump, ether is added to the residue and thesew dest lution is washed with water, excess .dilute sul- Iuric acid, sodium bicarbonate and finally water.

Each aqueous washing is extracted with ether,

and the combined ether solutions are dried and evaporated. The crude acetate remains .as a rather mobile orange oil.

Bicyclic ketone (.V) .The crude acetate (60 g.) and redistilled acetic anhydride (550 cc.) are heated .to l45f-150 C. in ,a parafiin .bath with stirring under reflux, with the exclusion oimoisture. Commercial zinc dust (559 g.) is added all ,at .once, and the mixture is stirred vigorously at this temperature for 8 minutes.

ether, the combined ether extracts are dried (MgSOr) and evaporated.- The residue is distilled roughly into two fractions:

(a) B. P. 68-98" C./0.4 mm. and (b) ,B. P. 117-137- C./0.4 mm.

Fraction (a) is redistilled slowly through a small Vigreux column to give the bicyclic ketone (V) as a colorless mobile liquid, B. P. 80-81 C./ 0.8 mm., 12 1.5167. On being seeded at room temperature (25 C.) is nearly completely solidifies, M. P. 26-29 C.

Hydromymethylene ketone (VI) .Commercial sodium methoxide (35 g.) is covered with dry benzene (175 cc.) and redistilled ethyl for-mate (87 cc.) is added in a thin stream to the stirred mixture at room temperature in a nitrogen atmosphere. Stirring is continued at room temperature for a further /2 hour, when the mixture is cooled in ice. The bicyclic ketone (35 g.) in dry benzene (175 cc.) is added dropwise during 45 minutes with ice-cooling. More benzene (175 cc.) is added, and stirring in nitrogen is continued for a further 12 hours at room temperature. About 30 minutes after the end of the addition a voluminous yellow gelatinous precipitate separates, which does not change in appearance when the reaction was terminated. Ether and iced dilute sulphuric acid are added, the aqueous layer is washed with ether, and the combined ethereal layers are washed with excess potassium hydroxide solution. The red-brown alkaline aqueous layer is washed once with ether, acidified with dilute hydrochloric acid, and extracted twice with ether. The latter ether washings are washed once with water, dried. and evaporated. The residue contains some formic acid, and is therefore distilled through a small Vigreux column. This yields the hydroxymethylene ketone (VI) as a yellow mobile liquid, B. P. 88-90 (J./0.()15-mm.,11. 15552.

More conveniently the hydroxymethylene compound may be isolated with benzene instead of ether. In that case the formic acid is removed when distilling oh; the benzene, and the crude undistilled hydroxymethylene ketone may be used for the next stage.

Ethyl vinyl keto'ne adduct (VII) .A Solution of freshly distilled ethyl .vinyl ketone (15.0 g.) and distilled hydroxymethylene ketone (VI:)

(39.0 g.) are dissolved in dry redistilled tertbutanol cc). The solution is cooled in ice,

the air displaced with nitrogen, and a solution of potassium tert-butoxide, prepared by dissolving potassium (600 mg.) in dry tert-butanol (22.5 cc.), is added. The solution iscooled until the butanol just starts to crystallize. The air is again displaced with nitrogen, and the solution is left at room temperature for 10 hours. On scratching a heavy precipitate separates; the mixture is ice-cooled, the adduct is filtered and washed with cold butanol. On being dried, the white sparkling plates melt at 98 C.

Tricyclic kctone (VIII) .-The crystalline ethyl vinyl ketone adduct (VII) (13.9 g.) is dissolvedin redistilled dioxan (760 cc.) and the solution is cooled in ice. A cooled solution of potassium hydroxide (19 g.) in water (760 cc.) is added, and the solution is allowed to stand at room temperature (ca. 30) for 3 hours with occasional shaking. The initially clear solution becomes turbid after a few minutes and a small upper layer separates. Ether and water are added, the aqueous layer is washed twice with ether, the combined organic extracts are washed with Water until neutral, and are then dried and evaporated. Thedioxan is finally removed at the water pump, when the residue on being cooled completely solidifies. Crystallization from methanol yields the tricyclic ketone. (VIII) as prisms, M. P. 70.5-72.5 C.

Tricyclic Icetone glycol (IX) ..-Osmium tetroxide (32.394 g.) is dissolved in Na-dried ether (350 cc.) or in benzene and ether (100 cc. benzene, to make a 27% solution, plus 250 cc. ether) and cooled. The 0504 solution is added to a cooled ether solution (730 cc.) of tricyclic ketone (VIII) (29.791 g.; 20 mg. in excess of calculated amount) with swirling. The solution is set aside at room temperature in a dark place for 5 to 8 days. The ether solution is decanted through a filter, and the complex is dissolved in methylene dichloride (5000s.) and shaken mechanically with a solution of mannitol (167 g.) and potassium hydrcxide (47.5 g.) in water (1250 cc.) for 1 hour or until the methylene chloride layer is very pale yellow. The methylene chloride layer is separated; the aqueous layer is saturated with sodium chloride and extracted four times with chloroform. The combined CH2C12-.CHC13 extracts are washed twice with saturated sodium chloride solution, dried with anhydrous Na2SO4, andconcentrated on the steam bath and in vacuo. The residual gum is triturated with benzene cc.) After cooling somewhat the white solids are filtered 01?. They melt at 150 C., and give the desired glycol (IX), M. P. 152156 C., after one recrystallization from CI-ICla-benzene.

Tricyclic isopropylidine ketone (X) .-The tricyclic ketone glycol (IX) (20 g.) is placed in a strong 2-liter Pyrex bottle with anhydrousCuSOr (100 g.) and dry acetone (2000 00.). The bottle is stoppered securely and shaken mechanically for 36 hours. The CLISCM is removed by filtration through sintered glass, and the acetone solution is shaken with a small amount of anhydrous K2003, filtered, and evaporated to dryness using a water aspirator. The residue, on crystallization from benzeneepetroleum ether, gives the isopropylidene compound (X), M. P. 95-.-98 C.

Mono-unsaturated tricyclz'c isopropylidene ketone (XI) .-The tricyclic isopropylidene ketone (X) (14.72? g.) is stirred in an atmosphere of hydrogen ,in-the presence of prereduced 2% pal.- ladium on strontium carbonate catalyst (l-.3 g in lull-cc. Ila-dried benzene. lnjlhours 25minutes, 1224 cc; hydrogenhas: been absorbed by which time the absorption of hydrogen hashecome drastically slowerand the reduction is stopped. The catalyst is filtered off through a sintered lass funnel, and washed with reagent grade benzene, and most .of the benzene is re v moved in vacuo. The residual solution is diluted with petroleum ether and the mono-unsaturated tricyclic isopropylidene ketone (XI) separates as 1 ature for 30 minutes, and'a solution'of the mono unsaturated'tricycl-ic isopropylidene ketone (24 g.) in dry benzene (150 cc.) is added. Stirring at room temperature is continued for about 1 hour or until the mixture has solidified to a gelatinous mass. After standing under nitrogen overnight, phosphate bufier solution (1406 cc.; 156 cc. 0.7M KH2PO4 plus 1250 cc. 0.7M Na2HPO4) is added with stirring, and the layers are separated. The pH of the aqueous layer is adjusted to pH 8 by adding a few cc. of the KH2PO4 solution, if necessary. The solution is extracted with ether 4 times, the combined organic layers are dried with Na-2SO4 and concentrated to drynes on the steam bath and in vacuo. The crude hydroxymethylene compound (XII) solidifies when all the solvent is removed.

Methylanilino derivative (XIII) .-The crude hydroxymethylene compound (XII) (29 g.) is dissolved in methanol (275 cc.) and methylaniline (57 cc.). After standing overnight the yellow crystalline methylanilino compound (XIII) is filtered ofi and washed with petroleum ether until the odor of methyl aniline can not be detected. It melts at 218-2225 C.

Cyanoethyl derivatives (XIVa and XIVb).- The methylanilino derivative (XIII) (30.2 g.) is dissolved by warming in a mixture of dry benzene (500 cc.) and dry t-butanol (1000 cc.). Acrylonitrile (13.2 g.) and Triton B (48.5 cc. of a 3.5% solution in t-butanol+3.5 cc, water) are added. The air is displaced by nitrogen and the reaction mixture is left at 50 C. for 45 hours. The solvents are removed in vacuo and the dark red residue is eluted several times with ether (ca. 400 cc.) to separate insoluble acrylonitrile polymer. Evaporation of the ether leaves the stereoisomeric cyanoethyl derivatives (XIVa and XIVb) as an orange gum.

C'arboxyethyl derivatives (XVa and XVb). The cyanoethyl derivatives (XIVa and XIVb) are preferably not separated but are converted to the corresponding carboxyethyl derivatives by vigorous basic hydrolysis. The mixture of (XIVa and XIVb) (:ca. 35 g.) is refluxed for 7 hours under nitrogen with potassium hydroxide (40 g.) and water (250 cc.).

Extraction with ether affords a small quantity of mono-unsaturated tricyclic isopropylidene ketone XI. Acidification of the aqueous layer with cold dilute (1:10) hydrochloric acid in the presence of ether followed by two ether extractions, drying and thorough removal of volatile materials gives a crude mixture of the stereoisomeric acids (XVa and XVb). Repeated trituration with ether causes the precipitation of isomer (XVa), M. P. 148150 C. (labile form) and .170-

10 173 :C. (stable form). Crude isomer (XVblis left as an amber gum on evaporation of the ether.

Enol Zactone (XVI) Crude. isomer (XVb) (10.7 g.) anddistilled acetic anhydride (80 cc.) are refluxed for 2 hours under nitrogen. Sodium acetate (0.1 g.) is added and, refluxing is con tinued for 2 hours more. Most of the acetic anhydride is removed in vacuo. Ether is added and the ether solution is washed withdilute sodium carbonate solution and water. Evaporation of the dried ether extract leaves a residue which partially crystallizes on addition of ether, to give crude enol lactone (XVI), M.'P. 185-210 C. Further crops of less pure (XVI) -may be obtained. The highest M. P. of this compound has been 240 C. (dec.), but material melting above 175 C. is satisfactory for further reaction.

D-homosteroid (XVII) .The enol .lactone (XVI) (2.18 g.), M. P. 185-210 0., is dissolved in dry benzene (40 cc.) and dry ether (40 cc.) under nitrogen. The mixture is cooled to 18 C. and a solution of methylmagnesium bromide in dry ether (21.3 00.; 0.285 N) is added dropwise with vigorous stirring over 2-3 hours. Dilute hydrochloric acid 00., 1:10) is added rapidly with stirring. The layers are separated and the aqueous layer washed with ether. The combined ether layers are washed with a little cold Water, dried and the solvent removed. The solid residue is refluxed for 2 hours under nitrogen with methanol (180 00.), water (20 cc.) and sodium hydroxide (1.95 g.). Saturated salt solution is added, and the product is extracted with ether. The dried extract on evaporation gives the D- homosteroid (XVII), which on crystallization from ethanol or benzene-ligroin has M. P. 199- 202 C.

Dialdehyde (XVIII) .-The D-homosteroid (XVII) (2.10 g.) is dissolved in pure dioxan (175 cc.), and periodic acid (4.1 g.) in water 8 cc.) is added. The homogeneous solution is allowed to stand at room temperature in a nitrogen atmosphere for 15 hours; most of the dioxan is then removed in vacuo, Water is added to the residue, and the product is extracted with ether. The dried extract is evaporated to yield the crude dialdehyde as a crystalline residue, which on crystallization from ether has M. P. 128-132 C.

Steroid (XIXa).-Heating the dialdehyde (XVIII) in solution recloses ring D to give the 17-a1-dehyde steroid ()flXa). The dialdehyde (XVIII) (1.87 g.) is dissolved in pure dioxan cc.) containing a trace of hydroquinone. Pure water (64 cc.) is added, and the solution" is heated in sealed glass tubes in a nitrogen atmosphere for 7%; hours at C. Ether is then added, the solution is Washed with sodium bicarbonate solution and Water, and is dried and evaporated. Addition of methanol causes the precipitation of the steroid (XEXa), M. P. C. The mother liquors are sublimed at 1( 0/10- mm., and the sublimate with methanol gives a further crop of (XIXa). The combined crops on crystallization from methanol give pure (XIXa), M. P. 171-173 C. The mother liquors, after the second crop of the steroid has been removed, give further crops of crystalline material. Recrystallization of these from aqueous methanol gives impure isomer (XIXb), M. P. 145-150 C.

The dialdehyde (XVIII) may also be converted into the tetracyclic 17-aldehyde (XIXa) in good yield by heating a solution in benzene at 60 C.

manner:

GOmpar-isoriof derivatives of the fl -aldehyde withsimilar derivatives of the naturally occurring steroid hormones ofthe adrenal cortex; such' as Kendalls compound E,- showsthat the ll' ald'ehydeis identical in steric configuration with-the natural-steroid hormones.

This application is a continuation-in-part of my application Serial No. 220,977 filed April 13-, 1951 Subject matter disclosed in" this application is alsoclaimed inmy applications Serial Nos; 269,328 and 269330.

I claim:

1. The method which comprises treating 1- formyl --1 ()9- propionylethyll -2 keto --10-- methyl#1,2 5;8;9,l 0--hexahydronaphthalene=with a dehydrating condensing agent and recovering hydrophenanthrenetherebwproduced;

2. The method which comprises treatingr 1- formyl -'1 (:p propionylethyl) 2 keto 10 methyl-1,2;5;8;9;I0-iiexahydronaphthalene with potassium hydroxide in an aqueous organic solvent and recovering the 1',1'4-dimetny1-2'-keto- 2,3,4,5,8;l2-,18,1 4 oetahydrophenanthrene: thereby produced.

octahydrophenanthrene.

ROBERTB'; WOODWARDZ References Cited in; the-"me of this patent STATESPATEN'IS Number Name Date 2,406,652 Ballard-$211.10"- Aug; 27, 1946 2,542,223 Wendler et-al. Febi20, 1951 

1. THE METHOD WHICH COMPRISES TREATING 1FORMYL - 1 - (B -PROPIONYLETHYL) -2 - KETO - 10 METHYL-1,2,5,8,9,10-HEXAHYDRONAPHTHALENE WITH A DEHYDRATING CONDENSING AGENT AND RECOVERING THE 1,14-DIMETHYL-2-KETO-2,3,4,5,8,12,13,14-OCTAHYDROPHENANTHRENE THEREBY PRODUCED.
 3. 1,14-DIMETHYL-2-KETO-2,3,4,5,8,12,13,14-OCTAHYDROPHENANTHRENE. 